Gpr65 modulators

Abstract

One aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (Formula (I)) wherein: ring B is: a monocyclic aromatic group; or a monocyclic or bicyclic heteroaromatic group, each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO2-alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkoxy and alkoxy; a is a single bond, Z is NR 7 , b is a double bond and Y is CR 8 ; or a is double bond, Z is N, b is a single bond and Y is CR 8 R 9 ; X is selected from O and S; R 6 and R 7 are each independently selected from H, alkyl, cycloalkyl and hydroxyalkyl. R 8 and R 9 are each independently selected from H, F, alkyl, and haloalkyl; and R a and R b are each independently selected from H and alkyl. Further aspects of the invention relate to compounds of formula (I) for use as a medicament, particularly in the field of immuno-oncology, immunology, and related applications.

1 . A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         ring B is:
 a monocyclic aromatic group; or 
 a monocyclic or bicyclic heteroaromatic group, 
 
         each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, haloalkyl, alkyl, haloalkoxy and alkoxy; 
         a is a single bond, Z is NR 7 , b is a double bond and Y is CR 8 ; or 
         a is double bond, Z is N, b is a single bond and Y is CR 8 R 9 ; 
         X is selected from O and S; 
         R e  and R 7  are each independently selected from H, alkyl, cycloalkyl and hydroxyalkyl. 
         R 8  and R 9  are each independently selected from H, F, alkyl, and haloalkyl; and 
         R a  and R b  are each independently selected from H and alkyl. 
       
     
     
         2 . A compound according to claim wherein R a  and R b  are both H 
     
     
         3 . A compound according to  claim 1 or claim 2  which is of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 4 , and R 5  are each independently selected from H, CN, alkyl, alkoxy, haloalkyl, OH, and halo; 
 R 2  and R 3  are each independently selected from H, halo, CN, alkoxy, haloalkyl, haloalkoxy, alkyl, aryl, heteroaryl, O-aryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, alkyl, haloalkoxy and alkoxy. 
 
     
     
         4 . A compound according to  claim 3 , wherein R 2  and R 3  are each independently selected from optionally substituted heteroaryl, F, Cl, Br, I, CN, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy and CO 2 -alkyl. 
     
     
         5 . A compound according to  claim 3 or claim 4 , wherein R 2  is selected from F, Cl and Br, and R 3  is selected from haloalkyl and a heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more groups selected from halo, alkoxy and haloalkoxy. 
     
     
         6 . A compound according to any one of  claims 3 to 5 , wherein R 1  and R 4  are both H. 
     
     
         7 . A compound according to any one of  claims 3 to 6 , wherein R 5  is selected from H, F, Me, MeO, Cl, OH and CN, and is preferably H or F, more preferably F. 
     
     
         8 . A compound according to any one of  claims 3 to 7  wherein R 1  and R 4  are H, R 2  is Cl, R 5  is F and R 3  is selected from haloalkyl and a heteroaryl group, wherein said heteroaryl group is optionally substituted by one or more substituents selected from halo, haloalky, alkoxy and haloalkoxy. 
     
     
         9 . A compound according to  claim 1 or claim 2  which is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
       
       wherein where n is 0 or 1 and X 1 -X 5  form a 5- or 6-membered heteroaromatic group containing at least one nitrogen atom, said heteroaromatic group being optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl. 
     
     
         10 . A compound according to  claim 9  wherein n is 1, and X 1 -X 5  form a 6-membered heteroaromatic group selected from pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl and 1,2,3,4-tetrazinyl, each of which is optionally substituted by one or more substituents selected from halo, CN, alkoxy, alkyl, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl. 
     
     
         11 . A compound according to  claim 9 , wherein n is 0, and X 1 -X 4  form a 5-membered heteroaromatic group selected from oxadiazoyl, thiadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, diazolyl, triazolyl, isoxazolyl, isothiazolyl, tetrazolyl, oxazolyl, and thiazolyl, and wherein said heteroaromatic group is optionally substituted by one or more substituents selected from halo, CN, alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocycloalkyl, O-heterocycloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl and O-aryl. 
     
     
         12 . A compound according to  claim 11 , which is of formula (Ih), or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 -X 4  form a heteroaromatic group containing at least one nitrogen atom, wherein:
 X 1  is N or CR 1 ; 
 X 2  is N or CR 2 ; 
 X 3  is selected from NR 15 , O and S, where R 15  is H, alkyl or haloalky, preferably H; 
 X 4  is N or CR 4 ; and 
 R 1 , R 2  and R 4  are each independently selected from H, halo, CN, alkoxyl, alkyl, haloalkyl, aryl, heteroaryl and O-aryl, more preferably, H, halo, CN, alkoxyl, alkyl and haloalkyl. 
 
       
     
     
         13 . A compound according to  any preceding claim , which is of formula (I.1): 
       
         
           
           
               
               
           
         
       
       wherein B, X, Y, a, b, R a , R b , Z and R 6  are as defined in any of  claims 1 to 12 , or which is in the form of a mixture that is enantiomerically enriched with a compound of formula (I.1). 
     
     
         14 . A compound according to any one of  claims 1 to 12 , which is of formula (I.2): 
       
         
           
           
               
               
           
         
       
       wherein B, X, Y, a, b, R a , R b , Z and R 6  are as defined in any of  claims 1 to 12 , or which is in the form of a mixture that is enantiomerically enriched with a compound of formula (I.2). 
     
     
         15 . A compound according to  any preceding claim  wherein R 6  is selected from H, methyl and hydroxymethyl, and is more preferably H. 
     
     
         16 . A compound according to  any preceding claim  wherein a is a single bond, Z is NR 7 , b is a double bond and Y is CR 8 . 
     
     
         17 . A compound according to  claim 16 , wherein a is a single bond, Z is NH, b is a double bond and Y is CH. 
     
     
         18 . A compound according to  any preceding claim  wherein X is O. 
     
     
         19 . A compound according to any one of  claims 1 to 17  wherein X is S. 
     
     
         20 . A compound of formula (Ij), or a pharmaceutically acceptable salt or solvate thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         ring B is:
 a monocyclic aromatic group; or 
 a monocyclic or bicyclic heteroaromatic group, 
 
         each of which is optionally substituted by one or more substituents selected from halo, CN, OH, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, hydroxycycloalkyl, O-cycloalkyl, alkoxy, haloalkoxy, heterocycloalkyl, O-heterocycloalkyl, aryl, heteroaryl, O-aryl, NHCO-alkenyl and CO 2 -alkyl, wherein said aryl, heteroaryl, O-cycloalkyl and O-aryl groups are each optionally further substituted by one or more groups independently selected from halo, haloalkyl, haloalkoxy alkyl and alkoxy; 
         Y is CR 8 R 9 ; 
         R 8  and R 9  are each independently selected from H, F, alkyl, and haloalkyl; 
         R 10  is selected from alkyl, alkoxy, haloalkyl, halo, S-alkyl, SO-alkyl and SO 2 -alkyl; and 
         R a  and R b  are each independently selected from H and alkyl. 
       
     
     
         21 . A compound according to  claim 20  wherein ring B is as defined in any one of  claims 1 to 12 . 
     
     
         22 . A compound according to  claim 21  wherein R 10  is SO 2 -alkyl, more preferably, SO 2 -Me. 
     
     
         23 . A compound according to  any preceding claim  which is selected from the following: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and enantiomers thereof, and mixtures of enantiomers thereof, including racemic mixtures, and pharmaceutically acceptable salts and solvates thereof. 
     
     
         24 . A pharmaceutical composition comprising a compound according to any of  claims 1-23 , and a pharmaceutically acceptable diluent, excipient, or carrier. 
     
     
         25 . A compound according to any one of  claims 1-23 , or a pharmaceutical composition according to  claim 24 , for use as a medicament. 
     
     
         26 . A compound according to any one of  claims 1-23 , or a pharmaceutical composition according to  claim 24 , for use in treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 
     
     
         27 . A compound or pharmaceutical composition for use according to  claim 26 , wherein the use comprises modulating GPR65, preferably wherein the use comprises inhibiting GPR65 signalling. 
     
     
         28 . A compound or pharmaceutical composition for use according to  claim 26 or claim 27 , wherein the disorder is a proliferative disorder. 
     
     
         29 . A compound or pharmaceutical composition for use according to  claim 28 , wherein the proliferative disorder is a cancer, and is preferably a solid tumour and/or metastases thereof. 
     
     
         30 . A compound or pharmaceutical composition for use according to  claim 29 , wherein the proliferative disorder is a cancer selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukaemia (AML), triple negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, pancreatic adenocarcinoma, sarcoma, lung cancer, ovarian cancer and gliomas, preferably glioblastoma (GBM). 
     
     
         31 . A compound or pharmaceutical composition for use according to  claim 26 or claim 27  wherein the disorder is an immune disorder. 
     
     
         32 . A compound or pharmaceutical composition for use according to  claim 31 , wherein the immune disorder is an autoimmune disease. 
     
     
         33 . A compound or pharmaceutical composition for use according to  claim 32 , wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's thyroiditis), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis-dermatomyositis, systemic sclerosis (scleroderma), Sjogren's Syndrome, ankylosing spondylitis and related spondyloarthropathies, sarcoidosis, autoimmune hemolytic anemia, immunological platelet disorders, and autoimmune polyendocrinopathies. 
     
     
         34 . A compound or pharmaceutical composition for use according to  claim 33 , wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS). 
     
     
         35 . A compound or pharmaceutical composition for use according to  claim 26 or claim 27 , wherein the use comprises treating or preventing a disorder selected from asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 
     
     
         36 . A method of treating a disorder as defined in any of  claims 26 to 35 , comprising administering to a subject a compound as defined in any of  claims 1-23 , or a pharmaceutical composition as defined in  claim 24 . 
     
     
         37 . A compound as defined in any one of  claims 1-23 , or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to  claim 24 , for use in treating or preventing a GPR65-associated disease or disorder. 
     
     
         38 . Use of a compound as defined in any one of  claims 1-23 , or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a GPR65-associated disease or disorder in a subject. 
     
     
         39 . Use of a compound as defined in any one of  claims 1-23 , or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).